Dosage forms of risedronate

ABSTRACT

The present invention is directed to a novel enteric-coated oral dosage form of a risedronate active ingredient comprised of a safe and effective amount of a pharmaceutical compostion which is comprised of a risedronate active ingredient and pharmaceutically-acceptable excipients. Said dosage forms prohibit the exposure of the risedronate active ingredient to the epithelial and mucosal tissues of the buccal cavity, pharynx, esophagus, and stomach and thereby protects said tissues from erosion, ulceration or other like irritation. Accordingly, the said dosage forms effect the delivery to the lower intestinal tract of said human or other mammal of a safe and effective amount of the risedronate active ingredient, and substantially alleviate the esophagitis or esophageal irritation which sometimes accompanies the oral administration of risedronate active ingredients.

CROSS REFERENCE

This application is a Continuation Application of application U.S. Ser.No. 09/303,466 filed on Apr. 30, 1999, now U.S. Pat. No. 6,096,342 whichis a continuation of application U.S. Ser. No. 08/820,430 filed on Mar.12, 1997 (now U.S. Pat. No. 5,935,602), which is a continuation ofapplication Ser. No. 08/307,495 filed on Sep. 14, 1994 (now U.S. Pat.No. 5,622,721), which is a continuation of application Ser. No.07/796,151 filed on Nov. 22, 1991 (now abandoned).

TECHNICAL FIELD

The present invention relates to novel oral dosage forms of thediphosphonate compound, 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonicacid, hereinafter referred to as “risedronate”. Said novel dosage formsare enteric-coated and delay the release of the risedronate until thelower intestinal tract is reached, thereby protecting the epithelial andmucosal tissues of the mouth and the buccal cavity, the pharynx, thelarynx, and the esophagus from erosion, ulceration, or other likeirritation suffered by direct contact of these tissues with therisedronate active ingredient which may sometimes result from the oraladministration of risedronate. This invention further relates to amethod of treating or preventing diseases characterized by abnormalcalcium and phosphate metabolism using the novel enteric coated dosageforms described herein.

BACKGROUND OF THE INVENTION

Polyphosphonic acids and their pharmaceutically-acceptable salts havebeen proposed for use in the treatment and prophylaxis of a number ofpathological conditions which can affect humans or other mammals andinvolve calcium and phosphate metabolism. Such conditions may be dividedinto two broad categories:

1. Conditions which are characterized by anomalous mobilization ofcalcium and phosphate leading to general or specific bone loss orexcessively high calcium and phosphate levels in the fluids of the body.Such conditions are sometimes referred to herein as pathological hardtissue demineralizations.

2. Conditions which cause or result from deposition of calcium andphosphate anomalously in the body. These conditions are sometimesreferred to herein as pathological calcifications.

The first category includes osteoporosis, a condition in which bone hardtissue is lost disproportionately to the development of new hard tissue.Marrow and bone spaces become larger, fibrous binding decreases, andcompact bone becomes fragile. Osteoporosis can be subclassified asmenopausal, senile, drug induced (e.g., adrenocorticoid, as can occur insteroid therapy), disease induced (e.g., arthritic and tumor), etc.,however, the manifestations are essentially the same. Another conditionin the first category is Paget's disease (osteitis deformans). In thisdisease, dissolution of normal bone occurs which is then haphazardlyreplaced by soft, poorly mineralized tissue such that the bone becomesdeformed from pressures of weight bearing, particularly in the tibia andfemur. Hyperparathyroidism, hypercalcemia of malignancy, and osteolyticbone metastases are conditions also included in the first category.

The second category, involving-conditions manifested by anomalouscalcium and phosphate deposition, includes myositis ossificansprogressive, calcinosis universalis, and such afflictions as arthritis,neuritis, bursitis, tendonitis and other inflammatory conditions whichpredispose involved tissue to deposition of calcium phosphates.

In particular diphosphonates, like ethane-1-hydroxy-1,1-diphosphonicacid (EHDP), propane-3-amino-1-hydroxy-1,1-diphosphonic acid (APD), anddichloromethane diphosphonic acid (Cl₂MDP) have been the subject ofconsiderable research efforts in this area. Paget's disease andheterotopic ossification are currently successfully treated with EHOP.The diphosphonates tend to inhibit the resorption of bone tissue, whichis beneficial to patients suffering from excessive bone loss. However,EHDP, APD and many other prior art diphosphonates have the propensity ofinhibiting bone mineralization when administered at high dosage levels.

The compound risedronate is a more biologically potent diphosphonatecompound which can be administered at low dosage levels; these lowerdosage levels have resulted in a wider margin of safety and cause littleor no mineralization inhibition. It is believed that the decrease in theinhibition of bone mineralization which is exhibited by the low dosagelevels occurs because mineralization inhibition is predominately a massrelated physiochemical effect, whereas resorption inhibition resultsfrom a biological interaction with the cells. In addition, low dosagelevels are also desirable to avoid the gastrointestinal discomfort, likenausea, diarrhea, and abdominal pains, which are sometimes associatedwith the oral administration of disphosphonates.

Despite the low-dosage levels possible with risedronate, the oraladministration of the compound sometimes results in patient complaintsshortly after dosing; said complaints are usually characterized by thepatients as heartburn, esophageal burning, pain and/or difficulty uponswallowing, and/or pain existing behind and/or mid-sternum. It isbelieved that these complaints originate from esophagitis or esophagealirritation caused by the erosion, ulceration, or other like irritationof the epithelial and mucosal tissues of the upper gastrointestinaltract, generally the mouth through the esophagus, most generally theesophagus. It is hypothesized that said irritation results from therisedronate active ingredient coming in direct contact with thoseepithelial and mucosal tissues, resulting in the topical irritationthereof.

Accordingly, it became desirable to develop novel oral dosage forms ofthe risedronate compound which would prevent the release of risedronatecompound in the area of said tissues. Said novel oral dosage forms areenteric coated and delay the beginning of the release of risedronateuntil some point in the small intestine or large intestine is reachedand, thereby, provide protection to the tissues of the mouth, pharynx,and esophagus. Said novel enteric-coated oral dosage forms may be in theform of enteric-coated tablets or starch or gelatin capsules containingenteric-coated beads or particles.

SUMMARY OF THE INVENTION

The present invention is directed to a novel enteric-coated oral dosageform of a risedronate active ingredient comprised of a safe andeffective amount of pharmaceutical compostion which is comprised of arisedronate active ingredient and pharmaceutically-acceptableexcipients. Said dosage forms prohibit the release of the risedronateactive ingredient in the buccal cavity, pharynx, esophagus, and stomachthereby protects the epithelial and mucosal tissues thereof fromerosion, ulceration or other like irritation.

Accordingly, the novel dosage forms described herein effect the deliveryto the lower intestinal tract of said human or other mammal of a safeand effective amount of the risedronate active ingredient, andsubstantially alleviate esophagitis or esophageal irritation whichsometimes accompanies the oral administration of risedronate activeingredients.

The invention further comprises a method of treating diseasescharacterized by abnormal calcium and phosphate metabolism comprisingadministering to a human or other mammal afflicted with such a disease anovel oral dosage form as described herein.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention is directed to a novel enteric-coated oral dosageform of a risedronate active ingredient comprised of a safe andeffective amount of a pharmaceutical compostion which is comprised of arisedronate active ingredient and pharmaceutically-acceptableexcipients. Said dosage forms prohibit the release of the risedronateactive ingredient in the mouth, pharynx, and esophagus and therebyprotects the epithelial and mucosal tissues thereof from erosion,ulceration or other like irritation. In addition, said dosage formsinhibit the release of the risedronate active ingredient to the stomachand anterior duodenum.

Accordingly, the said dosage forms effect the delivery to the lowerintestinal tract of said human or other mammal of a safe and effectiveamount of the risedronate active ingredient, and substantially alleviateesophagitis or esophageal irritation which sometimes accompanies theoral administration of risedronate active ingredients.

The invention further comprises a method of treating diseasescharacterized by abnormal calcium and phosphate metabolism comprisingadministering to a human or other mammal afflicted with such a disease anovel oral dosage form as described herein.

A. The Risedronate Active Ingredient

The term “risedronate”, as used herein, denotes the diphosphonatecompound 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid and hasthe following structure:

The compound risedronate is further described in the followingpublications, all hereby incorporated by reference herein: EPO PatentApplication 0,186,405 of Benedict et al., Which is the EuropeanEquivalent of U.S. Pat. No. 5,583,122, granted Dec. 10, 1996 assigned toThe Procter & Gamble Co., published Jul. 2, 1986; and “An InternationalConference, Bisphosphonates: Current Status and Future Prospects, TheRoyal College of Physicians, London, England, May 21-22, 1990, organizedby IBC Technical Services.

The term “risedronate active ingredient” includes risedronate,risedronate salts, and risedronate esters, or any mixture thereof. Anypharmaceutically-acceptable, non-toxic salt or ester of risedronate maybe used as the risedronate active ingredient in the novel oral dosageforms of the present invention. The salts of risedronate may be acidaddition salts, in particular the hydrochloride, but anypharmaceutically-acceptable, non-toxic organic or inorganic acid saltmay be used. In addition, salts formed with the carboxylic acid groupmay be used, including, but not limited to, alkali metal salts (K, Na)and alkaline earth metal salts (Ca, Mg), the Ca— and Na— salts beingpreferred.

Particularly, other esters of risedronate which are suitable for use asthe active ingredient in the invention disclosed herein are straightchain or branched chain C₁-C₁₈ alkyl esters, including, but not limitedto, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl,heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl;straight chain or branched C₂-C₁₈ alkenyl esters, including, but notlimited to, vinyl, alkyl, undecenyl, and linolenyl; C₃-C₈ cycloalkylesters, including, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; aryl esters,including, but not limited to, phenyl, toluyl, xylyl, and naphthyl;alicyclic esters, including, but not limited to, menthyl; and aralkylesters, including, but not limited to, benzyl, and phenethyl.

Generally speaking, the proper selection of the risedronate activeingredient depends on the selected type of formulation, the diseasepattern, especially the site and type of the disease, and the desiredrelease of the active ingredient. In addition, the physical and chemicalcharacteristics of the active ingredient must be taken into account whenselecting suitable pharmaceutically-acceptable excipients for use in thenovel dosage forms containing the risedronate active ingredient.

The effective oral dose of the risedronate active ingredient depends onthe extent of the disease and for adults it usually amounts to fromabout 1 g to about 40 g daily, preferably from about 1 g to about 30 gdaily. When the dose is to be administered continuously, the preferreddose is from 1-15 mg/day, preferably from 1-10 mg/day. When the dose isto be administered cyclically, the dose is preferably from 5-40 mg/day,preferably from 10-30 mg/day.

B. Site of Delivery of the Risedronate Active Ingredient

A human or other mammal suffering from diseases or disorders involvingcalcium and phosphate metabolism can be successfully treated by thedelivery of the risedronate active ingredient to the lower intestinaltract of said human or other mammal, preferably to the small intestine.The novel oral enteric-coated dosage forms described herein effectdelivery to the lower intestinal tract; at the same time prohibits theundesired release of risedronate in the mouth, pharynx and/or theesophagus, as well as inhibits the release of the risedronate activeingredient in the stomach, thereby prohibiting the erosion, ulcerationor other like irritation of the epithelial or mucosal layers of thesetissues. Although delivery to the small intestine alone is generallypreferred, in some instances, however, it may be desired to deliver therisedronate active ingredient to the entire lower intestinal tract,beginning with delivery to the small intestine and continuing withdelivery to the large intestine; in other cases, delivery of therisedronate active ingredient to the large intestine only may bedesired. When utilizing the novel enteric-coated oral dosage formsdescribed herein, the pharmaceutically-acceptable excipients, coatingmethods, formulations, and/or thickness can be readily varied by oneskilled in the art.

The term “gastrointestinal tract” as used herein relates to thealimentary canal, i.e., that musculo-membranous tube about thirty feetin length, extending from the mouth to the anus. The term “uppergastrointestinal tract” as used herein means the buccal cavity, thepharynx, the esophagus, and the stomach. The term “lowergastrointestinal tract” as used herein means the small intestine, andthe large intestine.

The term “buccal cavity” means the mouth or oral cavity and is linedwith a mucous membrane which is continuous with the integument of thelips and with the mucous lining of the pharynx.

The term “pharynx” relates to that part of the upper gastrointestinaltract which is placed behind the nose, mouth and larynx. It is amucomembraneous tube about 4 inches in length and it is contiguousanteriorly with the mouth and posteriority with the esophagus and iscomposed of a mucous coat, a fibrous coat, and a muscular coat.

The term “esophagus” as used herein is a muscular canal about nineinches long extending from the pharynx to the stomach. The esophagus hasthree coats: an internal mucous coat surrounding the lumen, a middleareolar coat, and an external muscular coat.

The term “stomach” as used herein means that part of thegastrointestinal tract between the esophagus and the small intestine.

The term “small intestine” as used herein means that part of the lowergastrointestinal tract consisting of the duodenum, the jejunum, and theileum, i.e., that portion of the intestinal tract just distal to theduodenal sphincter of the fundus of the stomach and proximal to thelarge intestine.

The term “large intestine” as used herein includes that part of thelower gastrointestinal tract just distal to the small intestine,beginning with the cecum, including the ascending colon, the transversecolon, the descending colon, the sigmoid colon, and the rectum.

C. Novel Enteric-Coated Oral Dosage Forms for Delivery of theRisedronate Active Ingredient to the Lower Intestine

As stated hereinabove, the present invention is directed to novelenteric-coated oral dosage forms of the risedronate active ingredient toeffect delivery to the lower intestine of a human or other mammal,preferably to the small intestine, of a pharmaceutical compositioncomprised of a safe and effective amount of a risedronate activeingredient and pharmaceutically-acceptable excipients.

The novel oral dosage form may be either delayed-release formulations orsustained-release formulations; said oral dosage forms prohibit thedelivery of the risedronate active ingredient from the dosage form untilit reaches the lower intestinal tract of the individual. Accordingly,the tissues of the upper gastrointestinal tract, especially theepithelial and mucosal layers of the buccal cavity, the pharynx,esophagus and stomach from direct contact with the risedronate activeingredient. Said oral dosage form, therefore, substantially alleviatesthe esophagitis or esophageal irritation which sometimes occurs uponoral administration of pharmaceutical compositions containing arisedronate active ingredient. Accordingly, oral dosage forms suitablefor use herein may be enteric-coated delayed-release formulations orenteric-coated sustained-release formulations. The dosage forms may beformulated as tablets or capsules, along with suitable pharmaceuticalexcipients which are well-known to those skilled in the art aredescribed hereinbelow.

The term “pharmaceutical composition” means an oral dosage formcomprised of a safe and effective amount of a risedronate activeingredient and pharmaceutically-acceptable excipients. Thepharmaceutical compositions described herein are comprised of from 0.15%to 40.00%, preferably from 0.50% to 30.00% of a risedronate activeingredient and from 60.00% to 99.75%, preferably from 70.00% to about99.50% of pharmaceutically-acceptable excipients.

The phrase “safe and effective amount”, as used herein, means an amountof a compound or composition high enough to significantly positivelymodify the symptoms and/or condition to be treated, but low enough toavoid serious side effects (at a reasonable benefit/risk ratio), withinthe scope of sound medical Judgment. The safe and effective amount ofactive ingredient for use in the method of the invention herein willvary with the particular condition being treated, the age and physicalcondition of the patient being treated, the severity of the condition,the duration of the treatment, the nature of concurrent therapy, theparticular active ingredient being employed, the particularpharmaceutically-acceptable excipients utilized, and like factors withinthe knowledge and expertise of the attending physician.

The term “pharmaceutically-acceptable excipients” as used hereinincludes any physiologically inert, pharmacologically inactive materialknown to one skilled in the art, which is compatible with the physicaland chemical characteristics of the particular risedronate activeingredient selected for use. Pharmaceutically-acceptable excipientsinclude, but are not limited to, polymers, resins, plasticizers,fillers, lubricants, solvents, co-solvents, buffer systems, surfactants,preservatives, sweetening agents, flavoring agents, pharmaceutical gradedyes or pigments, and viscosity agents. All or part of thepharmaceutically-acceptable excipients contained in the pharmaceuticalycompositions described herein is used to make the enteric-coating whichis to be utilized in the novel oral dosage forms described herein.

The term “oral dosage form” as used herein means any pharmaceuticalcomposition intended to be administered to the gastrointestinal tract ofan individual via the mouth of said individual, and for purposes of thepresent invention, the delivered form can be in the form of a tablet,(preferably enteric-coated) containing granules or particles ofrisedronate active ingredient, or a capsule, (enteric-coated ornon-coated), containing enteric-coated beads or enteric-coated granulesof the risedronate active ingredient.

“Enteric-coated oral dosage form” as used herein relates to an oraldosage form containing a pharmaceutical composition as described hereinwhich utilizes an enteric coating to effect the release of therisedronate active ingredient in the lower intestinal tract. The entericcoated oral dosage from may be a compressed tablet (coated or uncoated)containing granules or particles of the risedronate active ingredient,which are themselves coated or uncoated. The enteric coated oral dosageform may be a gelatin capsule (coated or uncoated) containing beads orgranules of risedronate active ingredient which are themselves coated oruncoated.

The term “enteric-coating” as used herein relates to a mixture ofpharmaceutically-acceptable excipients which is applied to, combinedwith, mixed with or otherwise added to the risedronate activeingredients. The said coating may be applied to a compressed tablet, agelatin capsule, and/or the beads, granules, or particles of risedronateactive ingredient which are encapsulated into starch or gelatin capsulesor compressed into tablets.

Accordingly, the said enteric coating is preferably applied to acompressed tablet which contains particles or granules of activeingredient; however, in the event the particles or granules arethemselves enterically-coated before being compressed into a tablet,then the enteric coating of the compressed tablet itself is optional.The enteric coating is also applied to the beads or small particles ofactive ingredient which may be encapsulated into a starch or gelatincapsule. Said capsule may then be coated with said enteric coating, ifdesired. Because of their enteric coating, these novel dosage forms willprohibit the undesirable delivery of the risedronate active ingredientto the mucosal and epithelial tissues of the upper gastrointestinaltract, especially the mouth, pharynx and esophagus. Said coating alsoachieves the delivery of the active to the lower gastrointestinal tractat a point which can be manipulated by one skilled in the art bychoosing the excipients which make up the coating, its type, and/or itsthickness.

The term “delayed-release” as used herein refers to a delivery of arisedronate active ingredient which is effected by formulating theactive ingredient in a pharmaceutical composition so that the releasewill be accomplished at some generally predictable location in the lowerintestinal tract more distal to that which would have been accomplishedif there had been no alteration in the delivery of the activeingredient. The preferred method for effecting the delayed-release ofthe active ingredient involves coating (or otherwise encapsulating) saidactive ingredient with a substance which is not absorbed, or otherwisebroken down, by the gastrointestinal fluids to release said activeingredient until a specific desired point in the intestinal tract isreached. The most preferred type of delayed-release formulation for useherein is achieved by coating the tablet, capsule, or particles,granules, or beads of active ingredient with a substance which ispH-dependent, i.e., broken down at a pH which is generally present inthe small intestine, but not broken down at a pH which is generallypresent in the mouth, pharynx, esophagus or stomach. However, if it isdesired to effect the topical delivery via the oral administration of apharmaceutical composition containing the risedronate active ingredientto only the large intestine, or to the entire length of the intestinaltract beginning with the small intestine, then the selection of thecoating material and/or the method of coating or otherwise combining therisedronate active ingredient with the selected coating material orother pharmaceutically-acceptable excipients may be varied or altered asis described herein or by any method known to one skilled in the art.

The term “sustained-release” as used herein means the type of releasemechanism designed to effect the delivery of the active ingredient overan extended period of time, as contrasted to the delivery of adelayed-release type dose. The most preferred sustained-release typemethod for use herein involves the coating of granules of therisedronate active ingredient with a pH-independent coating, chosen fromthe group including, but not limited to ethylcellulose,hydroxypropylmethylcellulose, methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, and sodium carboxymethylcellulose. Varioussustained-release dosage forms could readily be fashioned by one skilledin the art which could achieve the delivery of the risedronate activeingredient to both the small intestine and the large intestine, to onlythe small intestine, or to only the large intestine, depending upon thechoice of the various coating materials, and/or coating thickness.

As stated hereinabove, the ultimate site of and/or the rate of topicaldelivery in the intestinal tract can be satisfactorily controlled by oneskilled in the art, by manipulating any one or more of the following:

(a) the active ingredient proper;

(b) the type of the coating, and the concomitant desirable thickness andpermeability (swelling properties) of said coating;

(c) the time-dependent conditions of the coating itself and/or withinthe coated tablet, particle, bead, or granule;

(d) the particle size of the granulated active ingredient; and

(e) the pH-dependent conditions of the coating itself and/or within thecoated tablet, particle, bead, or granule.

In particular, the solubility, acidity, and susceptibility to hydrolysisof the different risedronate active ingredients, such as acid additionsalts, salts formed with the carboxylic group, e.g., alkali metal salts,alkaline earth metal salts, etc., and esters, e.g., alkyl, alkenyl,aryl, aralkyl, may be used as guidelines for the proper choice. Inaddition, suitable pH-conditions might be established within the coatedtablets, particles, granules, or beads by adding a suitable buffer tothe active ingredient in accordance with the desired release pattern.

Besides the above mentioned variations in order to obtain the desiredrelease pattern, the excipients may also be varied, as long as they donot affect the activity of the particular risedronate active ingredientselected.

As stated hereinabove, pharmaceutically-acceptable excipients include,but are not limited to, polymers, resins, plasticizers, fillers,lubricants, solvents, cosolvents, surfactants, preservatives, sweeteneragents, flavoring agents, buffer systems, pharmaceutical-grade dyes orpigments, and viscosity agents.

The preferred solvent is water.

Flavoring agents among those useful herein include those described inRemington's Pharmaceutical Sciences, 18th Edition, Mack PublishingCompany, 1990, pp. 1288-1300, incorporated by reference herein. Dyes orpigments among those useful herein include those described in Handbookof Pharmaceutical Excipients, pp. 81-90, 1986 by the AmericanPharmaceutical Association & the Pharmaceutical Society of GreatBritain, incorporated by reference herein.

Preferred co-solvents include, but are not limited to, ethanol,glycerin, propylene glycol, polyethylene glycol.

Preferred buffer systems include., but are not limited to, potassiumacetate, boric, carbonic, phosphoric, succinic, malic, tartaric, citric,acetic, benzoic, lactic, glyceric, gluconic, glutaric and glutamic.Particularly preferred are phosphoric, tartaric, citric, and potassiumacetate.

Preferred surfactants include, but are not limited to, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrosemonoesters and lanolin esters and ethers.

Preferred preservatives include, but are not limited to, phenol, alkylesters of parahydroxybenzoic acid, benzoic acid and the salts thereof,boric acid and the salts thereof, sorbic acid and the salts thereof,chlorbutanol, benzyl alcohol, thimerosal, phenylmercuric acetate andnitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride,methyl paraben, and propyl paraben. Particularly preferred are the saltsof benzoic acid, cetylpyridinium chloride, methyl paraben and propylparaben.

Preferred sweeteners include, but are not limited to, sucrose, glucose,saccharin, and aspartame. Particularly preferred are sucrose andsaccharin.

Preferred viscosity agents include, but are not limited to,methylcellulose, sodium carboxymethylcellulose,hydroxypropyl-methylcellulose, carbomer, povidone, acacia, guar gum,xanthan gum and tragacanth. Particularly preferred are methylcellulose,carbomer, xanthan gum, guar gum, povidone and sodiumcarboxymethylcellulose.

Preferred fillers include, but are not limited to, lactose, sucrose,maltodextrin, and microcrystalline cellulose,

Preferred plasticizers include, but are not limited to, polyethyleneglycol, propylene glycol, dibutyl phthalate, and castor oil, acetylatedmonoglycerides, and triacetin.

Preferred polymers include, but are not limited to, ethylcellulose,hydroxypropylmethylcellulose phthalate, and cellulose acetate phthalate,polyvinyl acetate phthalate, and Eudragit L-30-D®, Eudragit L-100-55®and Eudragit S® 100, both manufactured by Rohm Pharma GmbH, Weiderstadt,West Germany, Cotteric, manufactured by Colorcon, Inc., West Point, Pa.

Preferred lubricants include, but are not limited to, magnesiumstearate, stearic acid, and talc.

Utilizing the novel oral dosage forms of the present invention, therisedronate active ingredient can be reliably delivered, specifically tothe entire lower intestinal tract, or any part thereof, preferably thesmall intestine, thereby prohibiting the undesired exposure ofrisedronate in the mucosal and epithelial tissues of the mouth, pharynx,and/or esophagus and inhibiting its release in the stomach. Said dosageforms render the risedronate active ingredient readily available forabsorption from the lower gastrointestinal tract and, there issubstantially no contact of the active ingredient upon the epithelialand mucosal tissues of the mouth, pharynx, esophagus, or stomach.Accordingly, the novel enteric-coated oral dosage forms of the presentinvention substantially alleviates the condition of esophagitis oresophageal irritation which sometimes results from the oraladministration of a pharmaceutical composition comprising a risedronateactive ingredient.

The most preferred oral dosage form which effects delivery to the smallintestine is comprised of a risedronate active ingredient and utilizes apH dependent enteric coating material made from a partly methylesterified methacrylic acid polymer. Said solid oral dosage form can bein the form of a enteric coated compressed tablet made of granules orparticles of active ingredient or a gelatin capsule which contain beadsor small particles of active ingredient which have themselves beenenterically coated.

While the coating method described immediately above is preferred, anyenteric coating which is insoluble at a pH below 5.5 (i.e., thatgenerally found in the mouth, pharynx, esophagus and stomach), butsoluble at pH 5.5 or above (i.e., that present in the small intestineand the large intestine) can be used in the practice of the presentinvention. Accordingly, when it is desired to effect the topicaldelivery of the risedronate active ingredient to the small intestine,any enteric coating is suitable which is wholly- or partially-insolubleat a pH below 5.5 and soluble at pH 5.5 or above.

The partly methyl esterified methacrylic acid polymer which is preferredfor use as the enteric coating must be applied to the compressed tablet,the gelatin capsule and/or the beads, particles or granules of activeingredient in a sufficient thickness so that the entire coating does notdissolve in gastrointestinal fluids at a pH below 5.5, but does dissolveat a pH of 5.5 or above. The dissolution or disintegration of theexcipient coating generally does not occur until the entry of the coateddosage form into the small intestine. In particular, there issubstantially no release of the risedronate ingredient upstream of theduodenum.

It is expected that any anionic polymer exhibiting the requisitepH-dependent solubility profile can be used as an enteric coating in thepractice of the present invention to achieve delivery of the risedronateactive ingredient to the lower intestine. The coating chosen must becompatible with the particular risedronate active ingredient selected.The preferred polymers for use in the present invention are anioniccarboxylic polymers. It is particularly preferred that the polymers areacrylic polymers, most preferably partly methyl-esterified methacrylicacid polymers, in which the ratio of anionic free carboxyl groups toester groups is about 1:1.

A particularly suitable methacrylic acid copolymer is Eudragit L®,particularly Eudragit L-30-D® and Eudragit 100-55®, manufactured by RohmPharma GmbH, Weiterstadt, West Germany. In Eudragit L-30,-D®, the ratioof free carboxyl groups to ester groups is approximately 1:1. Further,said copolymer is known to be insoluble in gastrointestinal fluidshaving a pH below 5.5, generally 1.5-5.5, i.e., that generally presentin the fluid of upper gastrointestinal tract, but readily soluble at pHabove 5.5, i.e., that generally present in the fluid of the lowergastrointestinal tract.

Another methacrylic acid copolymer which is suitable for use in coatingthe oral dosage forms and/or the granules, particles or beads of activeingredient which can be employed in the method of treatment describedherein, either alone or in combination with other coatings, is EudragitS®, manufactured by Rohm Pharma GmbH, Weiterstadt, West Germany.Eudragit S® differs from Eudragit L-30-D® only insofar as the ratio offree carboxyl groups to ester groups is approximately 1:2. Eudragit S®is also, like Eudragit L-30-D®, insoluble at pH below 5.5, generally1.5-5.5, such as that present in gastric juice, but, unlike EudragitL-30-D®, is poorly soluble in gastrointestinal fluids having a pH of5.5-7.0, such as that present in small intestinal juice. Said copolymeris soluble at pH 7.0 and above, i.e. that generally present in thecolon.

Eudragit S® can be used alone as a coating which would provide deliveryof the risedronate active ingredient beginning at the large intestine(more distal than the terminal ileum) via a delayed-release mechanism.In addition, Eudragit S®, being poorly soluble in intestinal juice belowpH 7.0, could be used in combination with Eudragit L-30-D®, soluble inintestinal juice above pH 5.5, in order to effect a delayed-release,composition which could be formulated to deliver the active ingredientat various segments of the intestinal tract; the more Eudragit L-30-D®used, the more proximal release and delivery begins and the moreEudragit S® used, the more distal release and delivery begins.

The coating can, and usually will, contain a plasticizer and possiblyother coating excipients such as coloring agents, talc, and/or magnesiumstearate, many of which are well known in the coating art. Inparticular, anionic carboxylic acrylic polymers usually will contain10-25% by weight of a plasticizer, especially dibutyl phthalate,polyethylene glycol, triethyl citrate andtriacetin. Conventional coatingtechniques such as spray or pan coating are employed to apply thecoating. As previously mentioned, the coating thickness must besufficient to ensure that the oral dosage form remains intact until thedesired site of topical delivery in the lower intestinal tract isreached.

As stated hereinabove, the solid oral dosage form may be in the form ofa coated compressed tablet which contains particles or granules of therisedronate active ingredient or of a gelatin capsule, coated oruncoated, which contains beads of the risedronate active ingredient,which themselves are enteric coated.

A. Enteric-Coated Tablets

One of the novel oral dosage forms of risedronate active ingredientwhich is preferred is enteric-coated compressed tablets. Tablets aremade combining, mixing or otherwise adding the risedronate activeingredient to suitable pharmaceutical excipients including, but notlimited to, sucrose, maltodextrin, lactose, microcrystalline cellulose,talc, magnesium stearate, crospovidone, and sodium starch glycolate.That mixture is then compressed into a tablet utilizing varioustableting techniques available to those skilled in the art. Thecompressed tablet is then coated with an enteric-coating material whichis made with suitable pharmaceutical excipients including, but notlimited to, Eudragit L®, Eudragit L-30-D®, Eudragit 100-55®, EudragitS®, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate,polyvinyl acetate phthalate cellulose acetate trimellatate, polyethyleneglycol 400-8000, triacetin, dibutyl phthalate, acetylatedmonoglycerides, triethyl citrate talc, and iron oxide. Theenteric-coating material is then applied to the compressed tabletutilizing numerous spraying techniques available to those skilled in theart.

The enteric-coating of the tablets is not soluble in the fluids of themouth, the pharynx, the esophagus, or the stomach and thereby prohibitsthe release of risedronate until the lower is intestine is reached,preferably the small intestine. Although it is not a preferred dosageform, one suitable dosage form which would effect delivery of therisedronate active ingredient to the lower intestinal tract and therebyproject the mucosal tissues of the mouth, esophagus, and stomach wouldbe an uncoated compressed tablet containing with enteric-coated beads,granules, or particles of the risedronate active ingredient.

For ease and cost-effectiveness of manufacture, however, the preferrednovel dosage form described herein consists of enteric-coated compressedtablets which contain uncoated particles or granules of the risedronateactive ingredient. In addition, some active ingredients are moisturesensitive and perform better if delivered in a tablet dosage form.

For the preferred coating method described herein utilizingmethylacrylate copolymers, when the desired site of delivery is thesmall intestine, it has been found that a coating thickness of between20 and 100 microns usually is required. Preferably, the coatingthickness is between 30 and 75 microns, and most preferably between 30and 50 microns. For Examples of a method suitable for use in coating acompressed tablet containing the risedronate active ingredient whichwill effect the delivery of said active ingredient to the smallintestine, see Examples I and II.

Another delayed-release type of compressed tablet suitable for achievingtopical delivery of the risedronate active ingredient to the largeintestine involves the use of a material, most preferably a resin, thedissolution of which is time-dependent, as opposed to thepreviously-mentioned methacrylic acid copolymer-type coatings which arepH-dependent. The delivery of said active ingredient to the smallintestine is accomplished by embedding individual particles of saidactive ingredient in a slowly-disintegrating or slowly-dissolving resinwhich has a particular dissolution profile such that the activeingredient remains substantially protected by the material while theparticles travel through the mouth, pharynx, esophagus and stomach of anindividual and that the active ingredient is substantially completelyexposed at the time the particles reach the small intestine. Inparticular, the preferred resin for use when employing this type ofexcipient material is a high-viscosity grade modified vinyl acetateresin such as Gelva C3-V30®, manufactured by The Monsanto Co., St.Louis, Mo. Other suitable resins are carboxylated polyvinyl acetates,polyvinyl/maleic anhydride copolymers, ethylcellulose, cellulosepolymers, methylacrylic acid/methyl methylacrylate copolymers, waxes,and mixtures thereof, including mixtures with shellac.

While the preferred oral dosage form described herein is a coateddelayed-release tablet containing a risedronate active ingredient, mostpreferably a release beginning in the small intestine, other methodsused to insure the delivery of the risedronate active ingredient to theintestinal tract can acertainly be utilized. For example, a suitabledosage form consists of enteric-coated granules or particles ofrisedronate in a sustained-release tablet and utilizes a polymer as thecoating material; said polymer is preferably chosen from the groupconsisting of ethylcellulose, hydroxypropylmethylcellulose,hydroxymethylcellulose, methylcellulose, hydroxycellulose, and sodiumcarboxymethylcellulose, preferably ethylcellulose.

Another sustained-release oral dosage form suitable for use in thedelivery of the risedronate active ingredient to the intestinal tract isa tablet characterized by a core comprising a risedronate activeingredient, preferably in the form of a weak base or a weak acid, uponwhich core there is provided a first, inner layer of a diffusionmembrane comprised of ethylcellulose and/or copolymers of polyethylacrylate, methyl methacrylate, trimethylammonium ethyl methacrylatechloride, or mixtures thereof. Further, on said inner layer there isprovided a second layer of an excipient material, preferably of anionicpolymers, fatty acids, or mixtures thereof, having a pk_(a) of about 4.5to about 7.0, preferably about 6.0 to about 6.5. When this outer layerhas been removed by dissolution upon passage of the composition into thesmall intestine with the higher pH, a slow but controlled release of therisedronate active ingredient from the core by diffusion through thediffusion membrane occurs due to the difference in concentration on eachside of said membrane.

B. Enteric Coated Beads or Granules

Another novel oral dosage form for the oral administration of therisedronate active ingredient consists of gelatin or starch capsuleswhich contain enteric-coated beads or granules of the active ingredient.The gelatin or starch capsules may themselves then be coated, ifdesired. The use of capsules which contain enteric coated beads isgenerally not preferred from a standpoint of manufacturing cost anddifficulty. However, some active ingredients which must be given inrelatively higher doses are sometimes difficult to compress intotablets. In addition, particularly when the active ingredient may beirritating to mucosal tissues, it may be preferred to deliver the drugin gelatin or starch capsules containing smaller particles, beads orgranules which are enterically coated versus enterically coated tablets.In addition, when ingested with food, tablets often sit in the stomachuntil the digestion of food causes the opening of the pyloric sphincterand pushes the tablet into the duodenum. When uncoated gelatin or starchcapsules are used, the gelatin or starch will break down in the stomach,releasing the enteric coated beads. The beads can move through thepylorus independently of the presence of food, and there is decreasedrisk of large amounts of the active risedronate agent sitting for anyperiod of time in direct contact with the epithelial and mucosaltissues. As used herein, “beads” refers to particles containing theactive ingredient which are prepared by applying the risedronate activeingredient to inert substrate spheres, or beads, preferably utilizing apolymer film.

The substrate bead, accordingly, is used as an inert substrate to whichthe risedronate active ingredient is applied. The beads may be made fromone, or a mixture of, a group selected from, but not limited to,sucrose, mannitol, lactose, dextrose, sorbitol, cellulose, and starch,most preferably sucrose and starch. The preferred size of the inertsubstrate beads is in the range of from 0.25 mm to 2.00 mm, preferably4.00 mm to 7.00 mm. In addition, suitable inert substrate beads may bepurchased as pre-prepared, for example, non-pareil PG beads,manufactured by Crompton and Knowles, Mahwah, N.J., or Edward MendellCo., Patterson, N.J. The risedronate active ingredient must be affixedto the inert substrate beads. The most preferred method of affixing theactive ingredient to the substrate bead is the use of a polymer film. Inaddition, if an active ingredient is chosen that is deliquescent, thepolymer film will serve to prevent the active from picking up moisture.If the active ingredient chosen is unstable in any way, the polymer filmmay provide some stability.

The polymer film preferably comprises a mixture ofhydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose and/or ethylcellulose, preferablyhydroxypropylmethylcellulose and ethylcellulose; and a suitableplasticizer. Plasticizers suitable for use in the film include, forexample, but are not limited to, polyethylene glycol, propylene glycol,triacetin, acetylated monoglycerides, phthalate esters, caster oil,dibutyl sebacate, triethyl citrate, and selected mixtures thereof. Thepreferred amount of plasticizer is 5 to 40%, more preferably 20 to 40%,of the amount of the polymer film.

In addition to the risedronate active ingredient, the polymer film maycontain optional fillers, pigments, and dyes as described hereinabove.

Preferably, the polymer or polymer mix can consist of any combinationthat offers protection against moisture pickup and/or oxygen transfer,and which is designed for immediate release of the active ingredient byintestinal juice. The amount of risedronate active ingredient to beapplied to the inert substrate beads may vary depending upon theconcentration desired in the finished product. However, the weight ofthe applied film on the substrate bead is between 5-50% weight gain,preferably between 5-25% weight gain, and most preferably 5-10% weightgain.

After the inert substrate beads are coated with the active ingredient,they must be enterically coated. Said enteric coating is appliedutilizing various spray techniques known to one skilled in the art. Saidcoating is applied to the beads of active ingredient at a thickness of20-100 microns, preferably 30-75 microns, most preferably 30-50 microns.

It may be desired to coat granules of the risedronate active ingredientinstead of spraying inert substrate beads with the active ingredient.Granules, as are used herein, means particles of active ingredient incombination with suitable pharmaceutically-acceptable excipients asdescribed hereinabove. Although is it preferable to encapsulate theenteric-coated granules, using starch or gelatin capsules, foradministration as an oral dosage from, the granules may also becompressed into tablets. Granules can be obtained by extrusion of amoist kneaded mass followed by spheronization and drying. Granules witha regular molding are preferred, for example, rod-shaped or cylindrical,particularly spherical. Spherical pellet-type granules are preferred,with a diameter between about 0.30 and 1.50 mm, preferably between about0.50 and 1.25 mm.

Suitable pharmaceutically-acceptable ingredients for making the granulesto be used in the novel dosage forms described herein include, but arenot limited to, lactose, cellulose, mannitol, sucrose, and starch.

The prepared granules of active ingredient are then coated with anenteric coating material prepared from the pharmaceutically-acceptableexcipients, utilizing various coating techniques known to those skilledin the art. Said coating is applied to said granules of activeingredient at a thickness of 20-100 microns, preferably 30-75 microns,most preferably 30-50 microns.

The following non-limiting examples serve to further illustrate thenovel oral dosage forms of the present invention.

EXAMPLE I Enteric-Coated Risedronate Tablets

Enteric-coated Risedronate tablets are made by preparing a coatingcomposition and compressed tablets containing the risedronate activeingredient, and then applying said coating composition to said tablets.

An enteric coating composition is prepared in the form of a lacquercontaining the following excipients, per tablet:

A. Enteric Coating Suspension

Excipients

Eudragit L-30-D ® 33.400 mg (manufactured by Rohm Pharma GmbH,Weiterstadt, West Germany) Polyethylene glycol 1.000 mg Talc 2.500 mgYellow Iron Oxide 0.034 mg Simethicone emulsion 0.800 mg Purified Water75.000 mg

The enteric coating is prepared utilizing the following method:

The talc and yellow iron oxide is added to a portion of purified waterand mixed until uniform. The polyethylene glycol 8000 and thesimethicone emulsion are added with continuous mixing. The resultingpigment suspension is next passed through a screen or a suitable mill tobreak up agglomerates. The Eudragit L-30-D® is screened and then addedto a suitable vessel and diluted with a portion of the purified water.The pigment suspension is then added to the diluted Eudragit suspensionand mixed until uniform.

In a suitable coating pan, the risedronate sodium tablets prepared asdescribed below are warmed to about 35°-40° C. The enteric coatingsuspension is sprayed onto the tablets at approximately 50 grams perminute. When the spray cycle is completed, the temperature is reducedand the tablets are removed and dried at 30°-40° C. for approximately 1hour.

A coating of 4 mg/cm² dried lacquer substance (i.e., about 45 micronsthick) is applied by spraying the above composition onto risedronateactive ingredient tablets, prepared in part B. below.

B. Risedronate Sodium Compressed Tablets

Onto 30 mg risedronate round-shaped tablets, each weighing 250 mg andeach containing:

Active ingredient Risedronate 30.00 mg* Excipients Lactose 156.00 mgMicrocrystalline Cellulose 60.50 mg Crosporidone 7.40 mg MagnesiumStearate 1.10 mg *This quantity of risedronate sodium is determined byassay and then adjusted to provide the designed dosage level ofrisedronate sodium on an anhydrous basis.

Tablets having the composition set forth above are prepared as follows:

The tablets are prepared by mixing the risedronate active ingredientwith the microcrystalline cellulose in a twin shell blender. The blendis passed through an oscillator equipped with a 60 mesh screen. Themilled blend is then returned to the turn shell blender along with thelactose and crospovidone and mixed until uniform. The magnesium stearateis added and mixed until adequate lubrication is achieved. Tablets arethen compressed on a rotary tablet press.

EXAMPLE II Capsules Containing Enteric-Coated Beads

Capsules containing enteric-coated beads are prepared by preparingenteric-coated beads, and then encapsulating them using a gelatincapsule. The beads consist of inert sugar spheres that are coated with apolymeric film which contains risedronate sodium and are preparedutlizing the procedure in part A below. The beads are nextenteric-coated utilizing the procedure described in part B below.

A. Risedronate Sodium-Coated Beads Component Mg/Capsule RisedronateSodium 30.0* Sugar Spheres, 20-25 115.6 meshHydroxypropylmethylcellulose 12.0 Polyethylene Glycol 3350 2.4 PurifiedWater 155.6 *This quantity of risedronate sodium is determined by assayand then adjusted to provide the designed dosage level of risedronatesodium on an anhydrous basis.

The Risedronate Coated Beads are prepared as follows:

The purified water is heated and the hydroxypropylmethylcellulose isslowly added. When the hydroxypropylmethylcellulose is dispersed, thepolyethylene glycol is added and the solution is allowed to cool to 30°C. or less. The risedronate sodium is cooled, then passed through amill, if needed, to break up agglomerates, and then mixed with thepolymer solution until uniform.

In a suitable coating column, the sugar spheres are warmed toapproximately 25° C. and then the risedronate coating suspensionprepared above is sprayed on by applying a coating of 5 mg/cm² driedlacquer substance about 50 microns thick to the beads. When the spraycycle is completed, the air is turned off and the beads are cooled toroom temperature.

B. Enteric-Coated Beads Component Mg/Capsule Risedronate Sodium 160.0Coated Beads (prepared in Part A above) Eudragit L-30-D ® (wet basis)106.0 Talc USP 16.90 Triethyl Citrate NF 3.20 Simethicone Emulsion USP2.10 Yellow Ferric Oxide NF 0.04 Purified Water 225.00

The talc is added and the yellow ferric oxide is added to a portion ofthe purified water and mixed until uniform. The triethyl citrate and thesimethicone emulsion is added with continued mixing. The resultingpigment suspension is then passed through a screen or a suitable mill tobreak up agglomerates. The Eudragit L30D® screened and then added to asuitable vessel and diluted with a portion of the purified water. Thepigment suspension is then added to the diluted Eudragit suspension andmixing is continued.

A talc slurry is prepared by dispersing the talc in a portion ofpurified water and mixing until the talc is uniform.

In a suitable coating column the risedronate sodium coated beads arewarmed to the appropriate temperature. The enteric coating suspensionhaving the composition described in part B is sprayed on the beads. Thetalc slurry is sprayed onto the enteric coated beads. When the spraycycle is completed, the air is turned off. The coated beads are storedat 40-50° C. for a minimum of 12 hours before encapsulating. The beadsare encapsulated utilizing a hard shell gelatin capsule using anappropriate capsule filler.

EXAMPLE III Enteric-Coated Risedronate Tablets

Enteric-coated risedronate tablets are prepared as described below,utilizing the method set forth in Example I.

A coating composition is prepared from a lacquer containing thefollowing excipients, per tablet:

Coateric ® 24.0 mg (manufactured by Colorcon, Inc., West Point, PATriacetin 3.0 mg Titanium Dioxide 3.0 mg Purified Water 167.0 mg

A coating weight of 10.0 w/w % dried lacquer substance (about 75 micronsthick) is applied by conventional pan coating to 10 mg risedronatetablets, so that oval-shaped tablets, each weighing 300 mg, result. Thecomposition of each tablet is as follows:

Active ingredient Risedronate Sodium 10 mg Excipients Sorbitol 142 mgStarch 1500 142 mg Silicon Dioxide 1 mg Stearic acid 15 mg

EXAMPLE IV Capsules Containing Enteric-coated Particles

Capsules containing enteric-coated particles are made by preparingparticles of the risedronate sodium active ingredient, and thenencapsulating them into a gelatin capsule. The particles have thefollowing composition:

Mg/Capsule Active Ingredient Risedronate Sodium 25 mg Excipients Lactose50 mg Microcrystalline Cellulose 50 mg

A mixture of risedronate sodium, lactose, and microcrystalline celluloseis moistened with water and kneaded, extruded, and speronized. The driedparticles are subsequently coated with enteric coating material preparedas described in Example III.

The Enteric-Coating has the following composition:

Component Eudragit L-30-D ® 90.0 Triethylcitrate 21.0 Antifoam AF 2.0Talc 7.0 Water 275.0

The particles having the composition as described hereinabove are coatedin a laminator with a coating mixture having the above composition.

The enteric coating is prepared utilizing the procedure set forth inExample II. In a suitable coating column, the particles are warmed toabout 25° C, and enteric coating solution is applied to the particles byspraying a coating of 5 mg/cm² dried lacquer substance about 50 micronsthick to the particles. When the spray cycle is completed, the air isturned of and the particles are cooled to room temperature.

The lacquered particles are powdered with talc and encapsulatedutilizing capsules (Capsule size 0), with a commercial capsule fillingmachine (Hafliger and Karg).

What is claimed is:
 1. A pharmaceutical composition comprising, from 0.15% to 40.00% by weight of a diphosphonate compound selected from the group consisting of: 2-(3-pyridyl)-ethane-1,1-diphonphonic acid; 2-(4-pryidyl)-ethane-1,1-diphosphonic acid; 2-(2-pyrdily)-hydroxethane-1,1-diphosphonic acid; 2-(3-pyridyl)-hydroxyethane-1-1,diphosphonic acid; and 2-(4-pyridyl)-hydroxyethan-1,1-diphosphonic and from 60.00% to 99.75% by weight of excipients comprising: lactose, microcrystalline cellulose, crospovidone, and magnesium stearate. 